Fluorinated steroids

ABSTRACT

Disclosed are the 22R and 22S epimers of compounds of the formula ##STR1## wherein X 1  represents a fluorine atom, and X 2  represents a hydrogen atom or a fluorine atom. Also disclosed are processes for the preparation of the compounds, pharmaceutical compositions comprising the compounds and methods of treatment of inflammatory and allergic conditions employing the compounds.

FIELD OF INVENTION

The present invention relates to novel anti-inflammatory andanti-allergic active compounds and to processes for their preparation.The invention also relates to pharmaceutical compositions containing thecompounds and to methods of the pharmacological use of the compounds.

The object of the invention is to provide an anti-inflammatory,immunosupressive and anti-allergic glucocorticosteroid or apharmaceutical composition thereof with high activity at the applicationplace, e.g. in the respiratory tract, on the skin, in the intestinaltract, in the joints or in the eye directing the drug to a delimitedtarget area, thereby inducing low glucocorticoid systemic effects.

BACKGROUND ART

It is known that glucocorticosteroids (GCS) can be used for localtherapy of inflammatory, allergic or immunologic diseases in respiratoryairways (e.g. asthma, rhinitis), in skin (eczema, psoriasis) or in bowel(ulcerative colitis, Morbus Crohn). With local glucocorticosteroidtherapy, clinical advantages over general therapy (with e.g.glucocorticosteroid tablets) are obtained, especially regardingreduction of the unwanted glucocorticoid effects outside the diseasedarea due to reduction of the necessary dose. To reach even higherclinical advantages, in e.g. severe respiratory airway disease, GCS musthave a suitable pharmacological profile. They should have high intrinsicglucocorticoid activity at the application site but also a rapidinactivation before or after uptake into the general circulation.

DISCLOSURE OF THE INVENTION

One object of the invention is to describe new GCS compounds. They arecharacterized by high anti-inflammatory, immunosupressive andanti-anaphylactic potency at the application site and particularly theyhave a markedly improved relationship between that potency and theactivity to provoke GCS actions outside the treated region.

The compounds of the invention are a 22R or 22S epimer of a compound ofthe general formula ##STR2## wherein X₁ and X₂ are the same or differentand each represents a hydrogen atom or a fluorine atom, provided that X₁and X₂ are not simultaneously a hydrogen atom.

The individual 22R and 22S epimers of the formula (I) can be elucidatedin the following way due to the chirality at the carbon atom in22-position: ##STR3## wherein X₁ and X₂ are as defined above.

An epimer 22R and 22S, respectively, of formula I above is by definitona compound containing not more than 2 per cent by weight, preferably notmore than 1 per cent by weight of the other epimer.

The preferred compounds of the invention are the 22R and 22S epimers ofthe structure ##STR4##

The preferred steroid has the R configuration at the 22 carbon atom.

Methods of Preparation

The 16α,17α-acetals of the formula I are prepared by reaction of acompound with the formula ##STR5## wherein X₁ and X₂ have the abovegiven definition, with an aldehyde of the formula ##STR6##

The reaction is carried out by adding the steroid to a solution of thealdehyde together with an acid catalyst, e.g. perchloric acid,p-toluenesulfonic acid, hydrochloric acid in an ether, preferablydioxane or in acetonitril.

The compounds of the formula I, are also prepared by transacetalisationof the corresponding 16α,17α-acetonides ##STR7## wherein X₁ and X₂ havethe above given definition, with an aldehyde of the formula ##STR8##

The reaction is carried out by adding the steroid to a solution of thealdehyde together with an acid catalyst, e.g. perchloric acid,p-toluenesulfonic acid, hydrochloric acid in an ether, preferablydioxane, or in acetonitril.

The reaction can also be performed in a reaction medium which is ahydrocarbon, preferably isooctane, wherein the solubility of thepregnane derivative (the 16,17-acetonide or the 16,17-diol) is less than1 mg/l, or in a halogenated hydrocarbon, preferably methylene chlorideor chloroform.

The reaction is catalysed by a hydrohalogen acid or an organic sulphonicacid such as p-toluenesulfonic acid.

The reaction is performed in the presence of small grains of an inertmaterial, such as glass, ceramic, sifted silicone dioxide (sand) orinert metal particles, such as granulated stainless steel or tantalum inthe reaction medium (when the reaction is performed in a hydrocarbonsolvent).

The 22R-epimer is so exclusively obtained that it can be sufficientlypurified to be used as a pharmaceutical substance by recrystallizationinstead of by the more expensive chromatographic procedure.

At the reaction procedure in hydrocarbons the steroid-catalyst complexwill form a big sticky lump which makes stirring and effective reactionimpossible.

To overcome this small grains of an inert material and effectivestirring is used to prevent the formation of a big lump and insteaddivide the steroid-catalyst complex into a thin layer around the grains.Thereby, the reactive surface will be much larger and the reaction withthe carbonyl compound proceeds very rapidly.

The inert grain material used in the process, preferably siliconedioxide (SiO₂), should consist of free-flowing small particles. Theparticles size is ranging from 0,1-1,0 mm, preferably 0,1-0,3 mm. Theamount used in the reaction will range from 1:3 to 1:50, preferably1:20.

With hydrohalogen acid is to be understood hydrofluoric, hydrochloric,hydrobromic and hydroiodic acid and the corresponding oxohalogen acids,such as perchloric acid.

The individual 22R and 22S epimers, which are formed at theacetalisation, possess practically identical solubility characteristics.Accordingly, they have turned out to be impossible to separate andisolate from the epimeric mixture by conventional methods for resolutionof stereoisomers, e.g. fractional crystallization. In order to obtainthe individual epimers separately, the stereoisomeric mixtures accordingto the formula I above are subject to column chromatography, thusseparating the 22R and 22S epimers in view of different mobility on thestationary phase. The chromatography may be carried out for instance oncross-linked dextran gels of the type Sephadex LH, e.g. Sephadex LH-20in combination with a suitable organic solvent as eluting agent.Sephadex LH-20, prepared by Pharmacia Fine Chemicals AB, Uppsala,Sweden, is a beadformed hydroxypropylated dextran gel wherein thedextran chains are cross-linked to give a three-dimensionalpolysaccharide network. As mobile phase, halogenated hydrocarbons, e.g.chloroform or a mixture of heptane-chloroform-ethanol in the proportions0-50:50-100:10-1, has successfully been used, preferably a 20:20:1mixture.

Alternatively, the chromatography may be carried out on microparticulatebonded phase columns, e.g. 10 μm octadecylsilane (μBondapak C₁₈) orμBondapak CN columns in combination with a suitable organic solvent asmobile phase. Ethanol water mixtures in the proportions 40-60:60-40 havesuccessfully been used.

The epimers 22R and 22S can also be obtained from a steroisomericmixture with the general formula ##STR9## wherein X₁ and X₂ have theabove given definition and R₃ is a carboxylic acid rest having astraight hydrocarbon chain having 1-5 carbon atoms preferably the21-acetate, after resolution by chromatography on Sephadex LH-20together with a suitable solvent or mixture of solvents, e.g.heptane-chloroform-ethanol in the proportions 0-50:50-10:10-1,preferably 20:20:1, as mobile phase. The separated and isolated epimers22R and 22S with the general formula (IV) above are submitted to basecatalyzed hydrolysis with hydroxides, carbonates or hydrogen carbonatesof alkaline metals, e.g. sodium or potssium hydroxide, sodium orpotassium carbonate or sodium or potassium hydrogen carbonate to givethe epimers 22R and 22S of the formula II and III respectively, above.The hydrolysis can alternatively be performed with an acid as catalyst,e.g. hydrochloric acid or sulfuric acid.

The compounds of the formula IV are prepared according to methodsdescribed in the companion application Ser. No. 08/094,100, filed Aug.24, 1993 now U.S. Pat. No. 5,614,514.

Pharmaceutical Preparations

The compounds of the invention may be used for different modes of localadministration dependent on the site of inflammation, e.g.percutaneously, parenterally or for local administration in therespiratory tract by inhalation. An important aim of the formulationdesign is to reach optimal bioavailability of the active steroidingredient. For percutaneous formulations this is advantagenouslyachieved if the steroid is dissolved with a high thermodynamic activityin the vehicle. This is attained by using a suitable system or solventscomprising suitable glycols, such as propylene glycol or 1,3-butandioleither as such or in combination with water.

It is also possible to dissolve the steroid either completely orpartially in a lipophilic phase with the aid of a surfactant as asolubilizer. The percutaneous compositions can be an ointment, an oil inwater cream, a water in oil cream or a lotion. In the emulsion vehiclesthe system comprising the dissolved active component can make up thedisperse phase as well as the continuous one. The steroid can also existin the above compositions as a micronized, solid substance.

Pressurized aerosols for steroids are intended for oral or nasalinhalation. The aerosol system is designed in such a way that eachdelivered dose contains 10-1000 μg, preferably 20-250 μg of the activesteroid. The most active steroids are administered in the lower part ofthe dose range. The micronized steroid consists of particlessubstantially smaller than 5 μm, which are suspended in a propellentmixture with the assistance of a dispersant, salt ofdioctylsulphosuccinic acid.

The steroid can also be administered by means of a dry powder inhaler.

One possibility is to mix the micronized steroid with a carriersubstance such as lactose or glucose. The powder mixture is dispensedinto hard gelatin capsules, each containing the desired dose of thesteroid. The capsule is then placed in a powder inhaler and the dose isinhaled into the patient's airways.

Another possibility is to process the micronized powder into sphereswhich break up during the dosing procedure. This spheronized powder isfilled into the drug reservoir in a multidose inhaler, e.g. Turbuhaler.A dosing unit meters the desired dose which is then inhaled by thepatient. With this system the steroid without a carrier substance isdelivered to the patient.

The steroid can also be included in formulations intended for treatinginflammatory bowel diseases, either by the oral route or rectally.Formulations for the oral route should be constructed so that thesteroid is delivered to the inflamed parts of the bowel. This can beaccomplished by different combinations of enteric and/or slow or controlrelease principles. For the rectal route an enema type formulation issuitable.

WORKING EXAMPLES

The invention will be further illustrated by the followingnon-limitative examples. In the examples a flow-rate of 2.5 ml/cm² ·h⁻¹is used at the preparative chromatographic runs. Molecular weights arein all examples determined with chemical ionization mass spectrometry(CH₄ as reagent gas) and the melting points on a Leitz Wetzlar hot stagemicroscope. The HPLC analyses (High Performance Liquid microscope. TheHPLC analyses (High Performance Liquid Chromatography) have beenperformed on a μBondapak C₁₈ column (300×3.9 mm i.d.) with a flow rateof 1.0 ml/min and with ethanol/water in ratios between 40:60 and 60:40as mobile phase, if not otherwise stated.

Example 16α,9α-Difluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione

A solution of 6α,9α-difluoro-16α-hydroxyprednisolone (2.0 g) in 1000 mlof absolute ethanol was added to a solution oftris(triphenylphosphine)rhodium chloride (2.2 g) in 500 ml of tolueneand hydrogenated at room temperature and atmospheric pressure for 7days. The reaction mixture was evaporated to dryness and methylenechloride (50 ml) was added. The solid precipitate was collected andrepeatedly washed with small portions of methylene chloride to give 1.8g of 6α,9α-difluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione.Molecular weight 414 (calc. 414.5).

Example 2 6α,9α-Difluoro-11β,21-dihydroxy-16α,17α-(1-methylethylidene)bis(oxy)!pregn-4-ene-3,20-dione

A suspension of 0.9 g of tris(triphenylphosphine)rhodium chloride in 250ml of degassed toluene was hydrogenated for 45 min at room temperatureand atmospheric pressure. A solution of 1.0 g of fluocinolone16α,17α-acetonide in 100 ml of absolute ethanol was added and thehydrogenation was continued for another 40 h. The reaction product wasevaporated and the residue purified by flash chromatography on silicausing acetone-petroleum ether as mobile phase to remove the main part ofthe catalyst. The eluate was evaporated and the residue further purifiedby chromatography on a Sephadex LH-20 column (72.5×6.3 cm) usingchloroform as mobile phase. The fraction 3555-4125 ml was collected andevaporated yielding 0.61 g of 6α,9α-difluoro-11β,21-dihydroxy-16α,17α-(1-methylethylidene)bis(oxy)!pregn-4-ene-3,20-dione. Melting point146°-151° C. α!_(D) ²⁵ =+124.5° (c=0.220; CH₂ Cl₂). Molecular weight 454(calc. 454.6). Purity: 98.5% (HPLC-analysis).

Example 3(22RS)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione

To a solution of freshly distilled butanal (0.5 g) and 0.4 ml ofperchloric acid (70%) in 100 ml of purified and dried dioxane, 1.8 g of6α,9α-difluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione wasadded in small portions with stirring during 30 min. The reactionmixture was stirred at room temperature for another 5 h. Methylenechloride (600 ml) was added and the solution was washed with aqueouspotassium carbonate and water, and dried over anhydrous magnesiumsulfate. The crude product obtained after evaporation was purified bychromatography on a Sephadex LH-20 column (76×6.3 cm) using chloroformas mobile phase. The fraction 3015-3705 ml was collected and evaporatedleaving 1.5 g of(22RS)-16α,17α-butylidenedioxy-6α,9α-difluoropregn-4-ene-3,20-dione.Molecular weight 468 calc. 468.5).

Example 4(22R)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione

6α,9α-Difluoro-11β,21-dihydroxy-16α,17α-(1-methylethylidene)bis(oxy)!pregn-4-ene-3,20-dione (100 mg), 0.03 ml ofbutanal, 2 ml of fine sand (SiO₂) and 4 ml of heptane were mixed at roomtemperature. Perchloric acid (70%; 0.1 ml) was added under vigorousstirring. The reaction mixture was stirred at room temperature foranother 5 h, cooled and filtered. The solid residue was washed with 4×15ml of aqueous potassium carbonate (10%) followed by 4×15 ml of water andthen stirred 4 times with 25 ml of dichloromethane. The combinedextracts were washed with water, dried and evaporated. The residue wasdissolved in a small amount of dichloromethane and precipitated withpetroleum ether (b.p. 40°-60° C.) yielding 75 mg of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dionemixed with 3% of the (22S)-epimer. The purity determined by HPLCanalysis was 98%. Molecular weight 468 (calc. 468.5).

Example 5 (22R)- and(22S)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione

(22RS)-16α,17α-Butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione(1.5 g) was resolved into its 22R- and 22S-epimers by chromatography ona Sephadex LH-20 column (76×6.3 cm) using a n-heptane-chloroform-ethanol(20:20:1) mixture as mobile phase. The fractions 1845-2565 ml (A) and2745-3600 ml (B) were collected and evaporated. The two products wereprecipitated from methylene chloride - petroleum ether. The product fromfraction A (332 mg) was identified with ¹ H-NMR and mass spectrometry tobe(22S)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dioneand the product from the B fraction (918 mg) as the 22R-epimer.

The epimers had the following properties. Epimer 22S: Melting point231°-44° C.; α!_(D) ²⁵ =+84.4° (c=0.096; CH₂ Cl₂); molecular weight 468(calc. 468.5). Epimer 22R: Melting point 150°-56° C.; α!_(D) ²⁵ =+120°(c=0.190; CH₂ Cl₂); molecular weight 468 (calc. 468.5). The purity ofthe epimers was determined by HPLC-analysis to be 95.7% for the22S-epimer (containing 1,2% of the 22R-epimer) and 98.8% for the22R-epimer (containing 0,7% of the 22S-epimer).

Example 6(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3-20-dione

A solution of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregna-1,4-diene-3,20-dione(4.0 g) and tris(triphenylphosphine)rhodium chloride (0.40 g) in 150 mlof absolute ethanol was hydrogenated at room temperature for 68 h. Water(150 ml) was added and the mixture filtered through a HV LP 0,45 μmfilter. The filtrate was partially evaporated. The precipitate formedwas filtered leaving 1.48 g of crude product which was purified on aSephadex LH-20 column (75×6.3 cm) using chloroform as mobile phase. Thefraction 3600-4200 ml was collected and evaporated and further purifiedon a Sephadex LH-20 column (75×6.3 cm) using heptane:chloroform:ethanol,20:20:1, as mobile phase. The fraction 9825-10500 ml was collected andevaporated yielding 0.57 g of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 468 (calc. 468.5). Purity: 96.5% (HPLC-analysis).

Another 220 ml of water was added to the filtrate above giving a furtherportion of solid product which after purification on a Sephadex LH-20column (75×6.3 cm) using chloroform as mobile phase (fraction 3795-4275ml) yielded 1.04 g of(22R)-16α,17α-butylidenedioxy-6α,9α-difluoro-11.beta.,21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 468 (calc 468.5). Purity 98.3% (HPLC-analysis).

Example 7 6α-Fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione

To a suspension of 1.4 g of tris(triphenylphosphine)rhodium chloride in300 ml of toluene was added a solution of 1170 mg of6α-fluoro-11β,16α,17α,21-tetrahydroxypregna-1,4-diene-3,20-dione in 250ml of absolute ethanol. The mixture was hydrogenated 22 h at roomtemperature and atmospheric pressure and evaporated. The residue wasprecipitated from acetone-chloroform yielding 661 mg of6α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione. Molecularweight 396 (calc. 396.5). Purity: 96.6% (HPLC-analysis).

Example 8(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione

6α-Fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione (308 mg) wasadded in portions to a solution of butanal (115 mg) and 70% perchloricacid (0.2 ml) in 50 ml of dioxane. The reaction mixture was stirred atroom temperature for 6 h. Methylene chloride (200 ml) was added and thesolution washed with 10% aqueous potassium carbonate and water anddried. The residue after evaporation was purified on a Sephadex LH-20column (87×2.5 cm) using chloroform as mobile phase. The fraction420-500 ml was collected and evaporated yielding 248 mg of(22RS)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Melting point 85°-96° C. α!_(D) ²⁵ =+119.8° (c=0.192; CH₂ Cl₂).Molecular weight 450 (calc. 450.6). Purity: 96.1% (HPLC-analysis). Thedistribution between the 22R- and 22S-epimers was 59/41 (HPLC-analysis).

Example 9 (22R)- and(22S)-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione

(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(225 mg) was resolved by preparative HPLC in portions on a μBondapak C₁₈column (150×19 mm) using ethanol:water, 40:60, as mobile phase. Thefractions centered at 265 ml (A) and 310 ml (B), respectively werecollected and evaporated. After precipitation from methylene chloride -petroleum ether fraction A yielded 68 mg of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Melting point 180°-192° C. α!_(D) ²⁵ =+138.9° (c=0.144; CH₂ Cl₂).Molecular weight 450 (calc. 450.6). Purity: 99.4% (HPLC-analysis).

Fraction B gave after precipitation 62 mg of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Melting point 168°-175° C. α!_(D) ²⁵ =+103.7° (c=0.216; CH₂ Cl₂).Molecular weight 450 (calc. 450.6). Purity: 99.5% HPLC-analysis).

Example 10 (22R)- and(22S)-21-Acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione

(22RS)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(68 mg) was dissolved in 1 ml of pyridine. Acetic anhydride (1 ml) wasadded and the reaction mixture stirred at room temperature for 1 h,poured into ice-water and-extracted with 3×25 ml of methylene chloride.The extract was dried and evaporated. The residue was chromatographed ona Sephadex LH-20 column (89×2.5 cm) using heptane:chloroform:ethanol,20:20:1, as mobile phase. The fractions 380-400 ml (A) and 420-440 ml(B) were collected and evaporated.

After precipitation from methylene chloride - petroleum ether fraction Ayielded 14 mg of(22S)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione.Melting point 179°-186° C. α!_(D) ²⁵ =+86.2° (c=0.188; CH₂ Cl₂).Molecular weight 492 (calc. 492.6). Purity: 97.5% (HPLC-analysis).

Fraction B gave after precipitation 20 mg of(22R)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dione.Melting point 169°-172° C. α!_(D) ²⁵ =+139.0° (c=0.200; CH₂ Cl₂).Molecular weight 492 (calc. 492.6). Purity: 97.9% (HPLC-analysis).

Example 11(22R)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione

To a solution of 20 mg of22R)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dionein 2 ml of ethanol, 2 ml of 2M hydrochloric acid was added. Afterstirring at 60° C. for 5 h the reaction mixture was neutralized withsaturated aqueous sodium hydrogen carbonate and extracted with 3×25 mlof methylene chloride. The combined extracts were washed with water,dried and evaporated. The residue was purified on a Sephadex LH-20column (87×2.5 cm) using chloroform as mobile phase. The fraction460-515 ml was collected and evaporated yielding 8 mg of(22R)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 450 (calc. 450.6). Purity 98.4% (HPLC-analysis).

Example 12(22S)-16α,17α-Butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione

To a solution of 14 mg of(22S)-21-acetoxy-16α,17α-butylidenedioxy-6α-fluoro-11.beta.-hydroxypregn-4-ene-3,20-dionein 2 ml of ethanol, 2 ml of 2M hydrochloric acid was added. Thereaction, isolation and purification was performed in the same way as inExample 11. The fraction 455-510 ml was collected and evaporated giving7 mg of(22S)-16α,17α-butylidenedioxy-6α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 450 (calc. 450.6). Purity: 98.6% (HPLC-analysis).

Example 13 9α-Fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione

A suspension of 3.0 g of tris(triphenylphosphine)rhodium chloride in1000 ml of degassed toluene was hydrogenated for 45 min at roomtemperature and atmospheric pressure. A solution of 5.0 g oftriamcinolone in 500 ml of absolute ethanol was added and thehydrogenation was continued for 48 h. The reaction mixture wasevaporated to dryness and suspended in 50 ml of methylene chloride.After filtration the solid phase was repeatedly washed with smallportions of methylene chloride and yielded after drying 4.4 g of9α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione. Molecularweight 396 (calc. 396.5).

Example 14(22RS)-16α,17α-Butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione

To a solution of freshly distilled butanal (100 mg) and 0.2 ml ofperchloric acid (70%) in 50 ml of purified and dried dioxane9α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione (340 mg) wasadded in small portions with stirring during 20 min. The reactionmixture was stirred at room temperature for another 5 h. Methylenechloride (200 ml) was added and the solution was washed with aqueouspotassium carbonate and water and dried over anhydrous magnesiumsulfate. The crude product obtained after evaporation was purified on aSephadex LH-20 column (72.5×6.3 cm) using chloroform as mobile phase.The fraction 2760-3195 ml was collected and evaporated yielding 215 mgof(22RS)-16α,17α-butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione.Molecular weight 450 (calc. 450.6). Purity 97.4% (HPLC-analysis).

Example 15 (22R)- and(22S)-16α,17α-Butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione

(22RS)-16α,17α-Butylidenedioxy-9α-fluoro-11β,21-dihydroxypregn-4-ene-3,20-dione(200 mg) was resolved by chromatography on a Sephadex LH-20 column(76×6.3 cm) using a heptane-chloroform-ethanol (20:20:1) mixture asmobile phase. The fractions 7560-8835 ml (A) and 8836-9360 ml (B) werecollected and evaporated. The product from fraction A (128 mg) wasidentified with ¹ H-NMR and mass spectrometry to be(22S)-16α,17α-butylidenedioxy-9α-fluoro-11β,21-dihydr-oxypregn-4-ene-3,20-dioneand the product from the B fraction (50 mg) as the 22R-epimer.

The epimers had the following properties. Epimer 22S: Melting point180°-190° C.; α!_(D) ²⁵ =+105.6° (c=0.214; CH₂ Cl₂); molecular weight450 (calc. 450.6). Epimer 22R: Melting point 147°-151° C.; α!_(D) ²⁵=+133.7° (C=0.196; CH₂ Cl₂); molecular weight 450 (calc. 450.6). Thepurity of the epimers was determined by HPLC-analysis to be 97.6% forthe 22S-epimer (containing 1,8% of the 22R-epimer) and 98.2% for the22R-epimer (containing 0,8% of the 22S-epimer).

Example 16 Pharmaceutical Preparations

The following non-limitative examples illustrate formulations intendedfor different topical forms of administration. The amount of activesteroid in the percutaneous formulations are ordinarily 0.001-0.2%(w/w), preferably 0.01-0.1% (w/w).

Formulation 1, Ointment

    ______________________________________                                        Steroid, micronized         0.025  g                                          Liquid paraffin             10.0   g                                          White soft paraffin                                                                           ad          100.0  g                                          ______________________________________                                    

Formulation 2, Ointment

    ______________________________________                                        Steroid                     0.025  g                                          Propylene glycol            5.0    g                                          Sorbitan sesquioleate       5.0    g                                          Liquid paraffin             10.0   g                                          White soft paraffin                                                                           ad          100.0  g                                          ______________________________________                                    

Formulation 3, Oil in Water Cream

    ______________________________________                                        Steroid                     0.025  g                                          Cetanol                     5.0    g                                          Glyceryl monostearate       5.0    g                                          Liquid paraffin             10.0   g                                          Cetomacrogol 1000           2.0    g                                          Citric acid                 0.1    g                                          Sodium citrate              0.2    g                                          propylene glycol            35.0   g                                          Water           ad          100.0  g                                          ______________________________________                                    

Formulation 4, Oil in Water Cream

    ______________________________________                                        Steroid, micronized         0.025  g                                          White soft paraffin         15.0   g                                          Liquid paraffin             5.0    g                                          Cetanol                     5.0    g                                          Sorbimacrogol stearate      2.0    g                                          Sorbitan monostearate       0.5    g                                          Sorbic acid                 0.2    g                                          Citric acid                 0.1    g                                          Sodium citrate              0.2    g                                          Water           ad          100.0  g                                          ______________________________________                                    

Formulation 5, Water in Oil Cream

    ______________________________________                                        Steroid                     0.025  g                                          White soft paraffin         35.0   g                                          Liquid paraffin             5.0    g                                          Sorbitan sesquioleate       5.0    g                                          Sorbic acid                 0.2    g                                          Citric acid                 0.1    g                                          Sodium citrate              0.2    g                                          Water           ad          100.0  g                                          ______________________________________                                    

Formulation 6, Lotion

    ______________________________________                                        Steroid                     0.25   mg                                         Isopropanol                 0.5    ml                                         Carboxyvinylpolymer         3      mg                                         NaOH                        q.s.                                              Water           ad          1.0    g                                          ______________________________________                                    

Formulation 7, Suspension for Injection

    ______________________________________                                        Steroid, micronized          0.05-10 mg                                       Sodium carboxymethylcellulose                                                                              7       mg                                       NaCl                         7       mg                                       Polyoxyethylene (20) sorbitan                                                                              0.5     mg                                       monooleate                                                                    Phenyl carbinol              8       mg                                       Water, sterile     ad        1.0     ml                                       ______________________________________                                    

Formulation 8, Aerosol for Oral and Nasal Inhalation

    ______________________________________                                        Steroid, micronized                                                                              0.1% w/w                                                   Sorbitan trioleate                                                                               0.7% w/w                                                   Trichlorofluoromethane                                                                          24.8% w/w                                                   Dichlorotetrafluoromethane                                                                      24.8% w/w                                                   Dichlorodifluoromethane                                                                         49.6% w/w                                                   ______________________________________                                    

Formulation 9, Solution for Atomization

    ______________________________________                                        Steroid                     7.0    mg                                         Propylene glycol            5.0    g                                          Water           ad          10.0   g                                          ______________________________________                                    

Formulation 10, Powder for Inhalation

    ______________________________________                                        A gelatin capsule is filled with a mixture of                                 ______________________________________                                        Steroid, micronized   0.1    mg                                               Lactose               20     mg                                               ______________________________________                                    

The powder is inhaled by means of an inhalation device.

Formulation 11, Powder for Inhalation

    ______________________________________                                        The spheronized powder is filled into a multidose powder                      inhaler. Each dose contains                                                   ______________________________________                                        Steroid, micronized   0.1    mg                                               ______________________________________                                    

Formulation 12, Powder for Inhalation

    ______________________________________                                        The spheronized powder is filled into a multidose powder                      inhaler. Each dose contains                                                   ______________________________________                                        Steroid, micronized   0.1    mg                                               Lactose, micronized   1      mg                                               ______________________________________                                    

Formulation 13, Capsule for Treating the Small Bowel

    ______________________________________                                        Steroid               1.0    mg                                               Sugar spheres         321    mg                                               Aguacoat ECD 30       6.6    mg                                               Acetyltributyl citrate                                                                              0.5    mg                                               Polysorbate 80        0.1    mg                                               Eudragit L100-55      17.5   mg                                               Triethylcitrate       1.8    mg                                               Talc                  8.8    mg                                               Antifoam MMS          0.01   mg                                               ______________________________________                                    

Formulation 14, Capsule for Treating the Large Bowel

    ______________________________________                                        Steroid               2.0    mg                                               Sugar spheres         305    mg                                               Aquacoat ECD 30       5.0    mg                                               Acetyltributyl citrate                                                                              0.4    mg                                               Polysorbate 80        0.14   mg                                               Eudragit NE30 D       12.6   mg                                               Eudragit S100         12.6   mg                                               Talc                  12.6   mg                                               ______________________________________                                    

Formulation 15, Rectal Enema

    ______________________________________                                        Steroid                 0.02   mg                                             Sodium carboxymethylcellulose                                                                         25     mg                                             Disodium edetate        0.5    mg                                             Methyl parahydroxybenzoate                                                                            0.8    mg                                             Propyl pharahydroxybenzoate                                                                           0.2    mg                                             Sodium chloride         7.0    mg                                             Citric acid anhydrous   1.8    mg                                             Polysorbate 80          0.01   mg                                             Water, purified ad      1.0    ml                                             ______________________________________                                    

Pharmacology

The selectivity for local antiinflammatory activity can be exemplifiedby the following airway model. A considerable fraction of inhaled GCS isdeposited in the pharynx and is subsequently swallowed ending up in thegut. This fraction contributes to the unwanted side effects of thesteroid since it is acting outside the area intended for treatment (thelung). Therefore, it is favourable to use a GCS with high localanti-inflammatory activity in the lung but low GCS induced effects afteroral uptake. Studies were therefore done in order to determine the GCSinduced effects after local application in the lung as well as afterperoral administration and the differentiation betweenglucocorticosteroid actions in the treated lung region and outside thisarea were tested in the following way.

Test Models

A. Test model for desired local antiinflammatory activity on airwaymucosa (left lung lobe)

Sprague Dawley rats (250 g) were slightly anaesthetized with Ephrane andthe glucocorticosteroid test preparation (suspended in saline) in avolume of 0.5 ml/kg was instilled into just the left lung lobe. Twohours later a suspension of Sephadex (5 mg/kg in a volume of 1 ml/kg)was instilled under slight anaesthesia in the trachea well above thebifurcation so that the suspension reached both the left and right lunglobes. Twenty hours later the rats were killed and the left lung lobesdissected out and weighed. Control groups got saline instead ofglucocorticosteroid preparation and saline instead of Sephadexsuspension to determine the weight of non-drug treated Sephadex edemaand the normal lung weight.

B. Test model for unwanted systemic effect by orally absorbedglucocorticosteroid

Sprague Dawley rats (250 g) were slightly anaesthetized with Ephrane andafter that the GCS test preparation in a volume of 0,5 ml/kg was givenorally. Two hours later a suspension of Sephadex (5 mg/kg in a volume of1 ml/kg) was instilled in the trachea well above the bifurcation so thatthe suspension reached both the left and the right lung lobes. Twentyhours later, the rats were killed and the lung lobes were weighed.Control groups got saline instead of glucocorticosteroid preparation andsaline instead of Sephadex suspension to determine the weight ofnon-drug treated Sephadex edema and the normal weight.

The results of the comparative study are given in Table 1. Thepharmacological profile of the tested compound of the invention wascompared to that of budesonide. The results demonstrate that thecompound according to example 6 shows a much higher localantiinflammatory activity than budesonide. Furthermore, the results alsodemonstrate a higher lung selectivity of the tested compound of theinvention compared to the selected prior art compound since the doserequired to inhibit lung edema (ED₅₀) by oral administration of theabove mentioned compound is 32 times higher and of budesonide 13 timeshigher than the dose needed to inhibit lung edema by local applicationto the lung of the drugs. (Budesonide 4000 and 300 nmol/kg), example 6,320 and 10 nmol/kg, respectively)

Thus it can be concluded that the compounds of the invention are wellsuited for local treatment of inflammatory disorders in the skin andvarious cavities of the body (e.g. lung, nose, bowel and joint).

                  TABLE 1                                                         ______________________________________                                        Effects of tested glucocorticosteroids in the Sephadex                        induced lung edema model in the rat. The results are given                    in relation to the corresponding control group given Sephadex.                Compound                                                                              Ed.sub.50 (left lung                                                                         ED.sub.50                                              according to                                                                          administration; nmol/kg)                                                                     (p.o administration; nmol/kg)                          examples no                                                                           Left lung lobe.sup.x)                                                                        lung.sup.x)                                            ______________________________________                                        Budesonide                                                                            300            4000                                                   6        10             320                                                   ______________________________________                                         .sup.x) ED.sub.50 = required glucocorticosteroid dose to reduce the edema     by 50%.                                                                  

We claim:
 1. A compound which is a 22R or 22S epimer of the structure##STR10##
 2. A compound according to claim 1 wherein the stereoisomericconfiguration at the 22 carbon atom is R.
 3. A pharmaceuticalcomposition for the treatment of inflammatory and allergic conditions inmammals, comprising as active ingredient an effective amount of acompound according to claim 1 or 2 in a pharmaceutically acceptablecarrier.
 4. A pharmaceutical composition according to claim 3 in dosageunit form.
 5. A method for the treatment of inflammatory and allergicconditions in mammals comprising administering to a host in need of suchtreatment an effective amount of a compound according to claim 1 or 2.